More on the Biological Evidence for “Mental Illness”

On January 10, 2017, I put up a post titled The Biological Evidence for “Mental Illness”. It was published simultaneously on Mad in America. The post was a response to an earlier comment from Carolina Partners in Mental Healthcare PLLC, which included the assertion “mental illnesses have a long history of biological evidence.” In my January 10 article, I challenged this assertion and pointed out that no such evidence existed. The article generated some comments, most of which were favorable. There was one comment, however, from Michael, who asserted:

“Your rebuttal that there are no scientific studies to these cases can be dismissed with a quick google search.”

In my response to Michael, I asked him to cite me some references to support this assertion. On January 15, Michael wrote back citing three studies: the first on the neurobiology of depression; the second on the neurobiology of “schizophrenia”; and the third on the neurobiology of “bipolar disorder”.

I examined these studies, and started to draft a response to Michael, but as I was writing, I realized that the subject matter warranted a wider audience and needed to be put up as a post. This is not because the studies cited are particularly compelling. As we shall see below, they are not. But rather, because what has happened here is something that occurs routinely in these debates. Psychiatry proponents claim there is evidence to support their position that “mental illnesses” are caused by biological malfunctions – but when pressed for references, they either don’t respond at all, or they dish up the kind of references cited by Michael.

From the point of view of Carolina Partners and Michael’s original assertion, this study is particularly easy to rebut. In fact, the authors do it for us. Here’s the conclusion:

“Major depressive disorder is an illness with significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain. Antidepressant pharmacotherapy is associated with restoration of the underlying physiology. Clinicians are advised to intervene with MDD using an early, comprehensive treatment approach that has remission as the goal.” [Emphasis added]

Note that the authors are stating clearly that the structural, functional, and molecular neurobiological alterations are consequences of depression, not causes.

. . . . . . . . . . . . . . . .

But the article has many additional points of interest. Here are some quotes:

“Although much information still needs to be attained, imaging and other methods have begun to elucidate the neurobiological abnormalities associated with MDD. In particular, several prefrontal and limbic structures and their interconnected circuits have been implicated in affective regulation (Figure 2). These neuroanatomical areas include the ventromedial prefrontal cortex (VMPFC), lateral orbital prefrontal cortex (LOPFC), dorsolateral prefrontal cortex (DLPFC), anterior cingulated cortex (ACC), ventral striatum (including nucleus accumbens), amygdala and the hippocampus. Abnormalities in these areas have been shown in patients with MDD compared with healthy controls and thus suggest a foundation for the symptomatic expression of MDD (24, 25). However, these deviations may be obscured or not present at the individual patient level and thus, these findings cannot necessarily be considered pathognomonic.” [Emphasis added]

Note the admissions that:

“…much information still needs to be attained…”
“…imaging and other methods have begun to elucidate…” [Emphasis added]
“…implicated in affective regular…” [implicated in is not synonymous with causative of]
“…suggest a foundation…” [Emphasis added]
“…deviations may be obscured or not present at the individual patient level…” [Emphasis added]

This doesn’t sound very definitive or convincing.

. . . . . . . . . . . . . . . .

“Combining the evidence from these genetic, cross-sectional, and clinical treatment studies suggests that morphological differences in the hippocampus may be a predisposing factor in MDD, but changes can also accumulate in the course of the disease and thereby create an obstacle to full recovery.”

The ever-present predisposing factor – not quite the same thing as a cause – but good enough to convey the impression of causality.

But look at the last phrase in the quote:

“…changes can also accumulate in the course of the disease and thereby create an obstacle to full recovery.”

What the authors are suggesting here is that depression causes neurological pathology “in the course of the diseases” and that this pathology could create an obstacle to full recovery. Of course the drugs and hi-voltage electric shocks to the brain that psychiatrists routinely use to “treat” depression also cause neurological pathology.

And lest it be feared that I’m cherry-picking quotes that are particularly vague and unconvincing, the word “may” occurs 21 times in the paper, e.g. “this abnormal activity pattern may be responsible for the manifestations of symptoms associated with MDD”; “Symptomatically, disruptions as a result of proinflammatory cytokines may be experienced as fatigue, loss of appetite and libido as well as hypersensitivity to pain.” The word “could” occurs three times and the word “suggest(s)” ten times.

Here’s the final sentence of the study:

“Once remission is attained, maintenance of effect may become the more appropriate term, rather than relapse prevention, to emphasise the necessity for an ongoing collaboration between patient and physician in order to maintain neurobiological homeostasis.”

And what do you think is going to happen in this “…ongoing collaboration between patient and physician…”?

Here’s a clue:

“Disclosures
Vladimir Maletic has served on the Speaker’s Bureau or has been a consultant for Eli Lilly and Company and Cephalon. He did not receive any financial compensation for his work on this manuscript. His co-authors are each employees and/or shareholders of Eli Lilly and Company”

And incidentally, according to Dollars for Docs, Dr. Maletic received $841,342 from pharmaceutical companies between August 2013 and December 2015. In 2015 alone, he received 460 payments from pharma companies for a range of activities including promotional speaking, honoraria, consulting, education, food and lodging, etc. According to his biography on Global Medical Education, he is a Professor of Neuropsychiatry and Behavioral Science at the University of South Carolina School of Medicine.

Here again, the authors themselves have provided the rebuttal of Michael’s assertion. The final section of the paper is Conclusions and Possibilities for Future Research. Here are the first two sentences.

“In conclusion, we now believe that the molecular genetics of schizophrenia are sufficiently advanced such that etiology-based studies of the neurobiology of schizophrenia are both justified and feasible. The field is still in its infancy, and we must struggle to integrate our rudimentary knowledge of schizophrenia genetics with our scarcely better developed understanding of normal human brain function.”

So, etiology-based studies of the neurobiology of “schizophrenia” are justified and feasible. Which, of course, is a clear admission that the evidence is not to hand.

Later in the same section there’s this gem:

“The genes associated with schizophrenia may have a spectrum of different pathogenic effects, altering neuronal development, neuronal plasticity, and signal transduction. While undoubtedly a great oversimplification, it may be of heuristic value to postulate that variations in particular genes can affect particular neurobiological processes (Figure 6), in turn causing specific phenotypes.” [Emphasis added]

So the genes associated with “schizophrenia” may have a spectrum of different pathogenic effects. This is very vague. The use of the word “may” clearly implies that they also may not have such effects. But in any event, the evidence for such effects is not adduced in the paper.

And the assertion “…it may be of heuristic value to postulate that variations in particular genes can affect particular neurobiological processes…in turn causing specific phenotypes”, simply means that the hypothesis that genetic variations affect neurobiological processes, which in turn cause psychiatric “symptoms” may have value in encouraging us to explore and learn, which isn’t particularly profound. Any hypothesis can act as a stimulus to explore and learn.

Here are three more quotes from the section headed Neuropathology:

“Neuropathological investigations of schizophrenia…have not found any evidence of the usual features of neurodegenerative diseases, such as inclusion bodies, dystrophic neuritis, or reactive gliosis. There is intriguing, though not always consistent, evidence of subtle cytoarchitectural anomalies in entorhinal gray matter…and in other corticolimbic regions, and an abnormally high frequency of aberrant neurons in the white matter underlying prefrontal cortex…temporal, and parahippocampal regions…While these findings remain open to various interpretations…together they provide suggestive evidence for subtle abnormalities in neurodevelopment in schizophrenia, such as disordered cortical neuronal migration, consistent with the observation of subtle behavioral, neurological, and morphologic abnormalities.” [Emphasis added]

“Gene expression array studies have compared the expression profiles, in a number of different brain regions, of schizophrenias and controls…These studies have yielded inconsistent results and still need to overcome the difficulties inherent in the usage of postmortem brain tissue.” [Emphasis added]

“These studies may allow us to reconceptualize our definitions of the psychiatric disorders, including schizophrenia, based on a better understanding of etiology and pathogenesis.”

They may indeed – but clearly the authors are not saying that the evidence is in. In fact, in the Introduction to the article, they stated that:

“We argue in this review that a definitive study of the neurobiology of schizophrenia is now possible.”

The definitive study is “now possible”! This paper is dated October 2006, more than ten years ago. Why haven’t we seen the definitive study yet? Could it be, could it possibly be, that psychiatry, driven by its own self-centered considerations, is barking up the wrong tree?

Once again, let’s start with the author’s own assessment of his paper. The Conclusion section begins:

“A broad assessment of the current literature was done to bring to light the underpinnings of mood disorders in general and BD in particular. These are stress-related conditions with overt expression in individuals with an underlying genetic vulnerability. Modern neuroscience is utilizing animal models and conducting human research with increasingly sophisticated methods to unravel their pathophysiology. Significant strides have been made in understanding the neurobiology of affective illnesses, and in this regard new targets and biomarkers have been identified. Diverse biological systems act in concert in perpetuating the disorders. While obstacles in research remain in the basic scientific and clinical domains, there is no doubt that a representation is emerging that is providing a consolidated view regarding the development of these intractable conditions. It is hoped that new knowledge will translate into novel therapeutic measures that have both preventive and curative value for patients with bipolar spectrum disorders.”

Note:

“Modern neuroscience is [working]… to unravel their pathophysiology.” The clear implication is that they haven’t unraveled it yet.

“Significant strides have been made in understanding the neurobiology of affective illnesses,”. This is not what researchers say when they’ve made the great discovery. They say Eureka!

“… new targets and biomarkers have been identified.”

Biomarkers sounds pretty good. After all, it is widely claimed by psychiatry proponents that the identification of the elusive biomarkers is just around the corner. It is widely promoted that the biomarkers, when discovered, will clinch the biological pathology issue once and for all. So is that what the author is saying here? Well, no.

It is clear from the text that what this author means by “biomarkers” is simply a biological factor that correlates to varying degrees with the bipolar label. The author presents a few examples, but for illustrative purposes, let’s examine just one: cortisol levels in the blood stream.

“Early in the trajectory of BD, episodes occur secondary to stress but there is blighted psychobiological resilience and defective coping that increase vulnerability to recurrent affective exacerbations with illness advancement.12 This impairment is principally provoked by the hypothalamic-pituitary-adrenal (HPA) axis, which does not function properly in patients with BD.13 Patients with BD have a hyperactive HPA axis, high levels of systemic cortisol, and nonsuppression of its circulating levels in the dexamethasone suppression test or the dexamethasone/corticotrophin-releasing hormone (DEX/CRF) test.14“

This is a bit technical, but here’s the translation:

In the early stages of those behaviors, thoughts, and feelings that psychiatrists label bipolar disorder, episodes of mania and depression occur in response to stress.

But, as more episodes occur, there also occurs blighted psychobiological resilience, which presumably means reduced psychological resilience coupled with impairment in general health. These deteriorations are provoked by the HPA axis, “which does not function properly in patients with BD”. Note the term provoked, which isn’t quite the same as caused. Also note the cautious wording in the final clause: “does not function properly in patients with BD”. At first glance, this seems to be saying that the malfunctions cause the “BD”. But when read more carefully, no such causal connection is stated or even implied. All that’s being asserted is that HPA malfunction and being labeled BP are correlated. The causation, if it exists at all, could go either way.

People labeled BP have high cortisol levels as measured by the two tests mentioned.

Note the vagueness: “seems to be” and “vulnerability”. Not quite the same as cause.

But there’s more. The evidence for the HPA “irregularities” is the elevated cortisol level, which, incidentally, is just an average figure. In the study cited, several of the BD “patients” had cortisol levels in the same range as the controls. But more importantly, it’s been common knowledge since the 50’s that high alcohol consumption is associated with high cortisol levels, and, according to DSM-IV:

“As the Manic Episode develops, there is often a substantial increase in the use of alcohol or stimulants which may exacerbate or prolong the episode.” (p 330)

This is echoed in DSM-5, which notes a

“…tendency for individuals with bipolar 1 disorder to overuse substances during an episode.” (p 131)

So the elevated cortisol may reflect nothing more than frequent heavy drinking.

. . . . . . . . . . . . . . . .

In general, Dr. Muneer makes no claim that a biological cause to “BD” has been established. Indeed, the paper is characterized by caution and guardedness in this matter. For instance:

“…it is probable that most of the cortisol-GR [glucocorticoid receptor]-related mechanisms alluded to above are a sign of the putative genetic underpinning.” [Emphasis added]

Putative means assumed or believed to be the case.

“Given that the mechanisms of HPA axis dysregulation are incompletely known at present, as is its role in dictating the risk of the disease in vulnerable subjects, current work is beginning to unravel the molecular targets of illness development and progression in BD.” [Emphasis added]

“In bipolar patients, major mood episodes of either polarity result in an inflammatory response that has been convincingly shown in several studies.” [Emphasis added]

So the “episodes” cause the biological malfunction rather than the other way round.

Under the heading LIMITATIONS, the author states:

“The following caveats should be kept in mind while deducing any inferences with respect to the neurobiology of BD:
1) Not all predisposed individuals are afflicted by BD, which underscore the issues of genetic epistasis and hitherto little known mechanisms that mediate resiliency.
2) There are large gaps in knowledge due to the absence of good animal models replicating BD.
3) Technological advances are needed to reproduce findings from animal research in human samples.”

Note the truly exquisite optimism in item 1 above. Not all the people who have the biological correlate in question go on to develop the thoughts, feelings, and actions which psychiatry labels BD. So these individuals must have some as yet unknown “mechanisms” that confer resilience. But the alternative perspective, that this is simply not a fruitful line of inquiry, isn’t even addressed.

SUMMARY

None of the three studies put forward by Michael as evidence that “mental illness” is biologically caused come even close to establishing this premise. Indeed, in each case, the authors are quite clear that the evidence for this premise is not to hand. The articles are essentially discussion papers which discuss the implications of previous research, and express the hope that more definitive findings will be available some time in the future.

Meanwhile, psychiatrists and their supporters continue to claim that “mental illnesses” are real illnesses caused by brain pathology, that need to be corrected by drugs and/or high voltage electric shocks. These assertions remain unsubstantiated despite decades of highly motivated and lavishly funded research. For these assertions to acquire even a semblance of validity, psychiatry needs to demonstrate convincingly that all (or at last the great majority) of the individuals “diagnosed” with a particular “mental illness” have a clear and identifiable neural pathology, and that the causation runs from the pathology to the problems of thinking, feeling, and/or behaving in question. Weak correlations to neurophysiological processes or genetic variations are irrelevant, as I showed in the original article.

And while psychiatrists, for self-serving reasons, continue their inane efforts to “unravel” the neurobiological causes of these so-called illnesses, more obvious natural causes are studiously ignored and neglected. Tampering irresponsibly with a person’s brain because he is depressed, while ignoring those features of his lifestyle and recent history that have been known from time immemorial to precipitate depression, is reckless folly.

About Phil Hickey

I am a licensed psychologist, presently retired. I have worked in clinical and managerial positions in the mental health, corrections, and addictions fields in the United States and England. My wife Nancy and I have been married since 1970 and have four grown children.

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